Table 2.
Types of overgrowth syndromes.
| Syndrome | Characteristics | Complications | Gene/locus | Tumor surveillance |
|---|---|---|---|---|
| Perinatal overgrowth | ||||
| Beckwith–Wiedemann spectrum | Macroglossia, organomegaly, macrosomia, hypoglycemia, omphalocele, and hemihyperplasia | Wilms tumor, hepatoblastoma (see surveillance), rhabdomyosarcoma, and neuroblastoma Risk for BWSp is increased with assisted reproductive technology |
11p15.5 | Renal US including the adrenals every 3 months from diagnosis until the age of 7 + biannual physical examination; abdominal US every 3 months from diagnosis to the age of 4 + alpha-fetoprotein level |
| Simpson–Golabi–Behmel | Similar to BWSp, except that distinct facial dysmorphism become prominent with age, and nipples anomalies X linked disorder, seen primarily in males |
Wilms tumor, hepatoblastoma (see surveillance), and neuroblastoma | GPC3 (X-linked, Xq26.2) | Similar to BWSp; risk for malignancy is believed to be higher than the population risk |
| Sotos | Increased growth parameters, characteristic facial features, learning disabilities, and/or intellectual disabilities Tall stature and joint laxity may mimic Marfan syndrome |
Seizures, neonatal jaundice, hypotonia, and cardiac anomalies; mild increased risk for Wilms tumor, hepatoblastoma, and neuroblastoma |
NSD1 (can result from small deletions on 5q35) NFIX for the similarly presenting Malan syndrome and SETD2 for the similarly presenting Luscan–Lumish syndrome |
None |
| Weaver | Similar to Sotos, except with excess loose skin and camptodactyly, and “Stuck-on” protruding chin | No increased malignancy risk Hypotonia, feeding difficulties, and ventriculomegaly |
EZH2 | None |
| DNMT3A-related | Similar to Sotos, except for round facies with thick eyebrows and prominent maxillary incisors. In contrast to Sotos, dysmorphic features increase with age | Seizures and cardiac anomalies | DNMT3A | None |
| Perlman | Macrosomia, macrocephaly, hypotonia, nephromegaly with nephroblastomatosis, abdominal wall weakness, and cryptorchidism | Post-natal mortality is ~87% Wilms tumor seen in about 1/3 of patients |
DIS3L2 | None |
| Segmental Overgrowth | ||||
| PTEN hamartoma tumor syndrome* | Macrocephaly, hamartomas, and intellectual disability BRR: pigmented macules on the penile shaft, and hamartomatous colonic polyps CS: trichilemmomas, papillomatous papules, and acral and plantar keratosis |
Increased risk for breast, thyroid, renal, and endometrial carcinomas Colonic hamartomas may cause intussusception |
PTEN | Breast—similar to BRCA 1/2 Endometrial—symptom based Colon—colonoscopy every 5 years starting at 35 years of age or 5–10 years prior to first familial case Thyroid—neck ultrasound at the age of 7 and then every 2 years Renal—ultrasound at 40 years of age and then every 1–2 years |
| PIK3CA-related segmental overgrowth∧ | CLOVES—Lipomas, macrodactyly, scoliosis, body asymmetry, and skin wrinkling MCAP—megalencephaly, hypotonia, and limb asymmetry |
Lipomas may cause cord compression, skeletal deformation Seizures |
PIK3CA (overactivation) | None |
| KTS and PWS% | KTS: Asymmetric capillary/lymphatic malformations and limb overgrowth of usually the lower extremity PWS: similar but also characterized by arteriovenous fistulae |
Varicosities, thrombophlebitis, pulmonary embolism. Arteriovenous fistulae may predispose to high output cardiac failure and distal arterial ischemia | PIK3CA (KTS) and RASA1 (PWS) | None |
| Proteus syndrome | Extremely rare progressively deforming asymmetric overgrowth with characteristic cutaneous (cerebriform) connective tissue nevi. Most commonly affect distal lower limbs. Cranial hyperostosis, severe scoliosis, and vascular malformations are also common |
Deep vein thrombosis and pulmonary embolism | AKT1 (overactivation) | None |
*
PTEN hamartoma tumor syndrome includes Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome (BRB), and Proteus-like syndrome.
∧
PIK3CA-related segmental overgrowth includes two distinct phenotypes: CLOVES, congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal, and spinal syndrome; MCAP, megalencephaly–capillary malformation.
%
KTS, Klippel–Trenaunay syndrome; PWS, Parkes–Weber syndrome.